Recent years have seen the global emergence of vancomycin-resistant enterococcus (VRE),1,2 and this threat to human health was seriously increased by the recent transfer of vancomycin resistance to the more dangerous pathogen S. aureus.3,4 The lack of alternative therapeutics for VRE has increased interest in developing new glycopeptide derivatives to circumvent vancomycin resistance.
Two viable approaches for optimizing known glycopeptide scaffolds have emerged—the chemical modification of existing scaffolds and/or sugar functional groups, and the chemoenzymatic diversification of sugar residues.2,5 However, each approach suffers from distinct limitations that have limited the exploration of structure—activity relationships. For instance, to demonstrate the importance of glycolipid moieties in overcoming resistance, Kahne et al. have replaced the natural non-lipid containing disaccharide of vancomycin with the 2′-N-acyldecanoyl glucosyl moiety from teicoplanin to provide activity against VRE.6 However, it remains unclear if the 2′ position of glucose is optimal for lipid attachment in teicoplanin and whether lipids other than straight-chain variants would provide potent activity when attached to glucose in teicoplanin-like compounds because of the difficulties associated with synthesizing glycopeptide analogs with alternative lipid attachments.
Accordingly, the need exists for methods and techniques for creating a novel library of compounds that circumvents vancomycin resistance.